For several decades nitroglycerin has been administered to humans as a vasodilating agent in the treatment of cardiovascular disease. By 1987, it had become established that nitroglycerin so administered is converted in the body to nitric oxide which is the pharmacologically active metabolite. Still more recently, nitric oxide has been shown to be formed in endothelial cells from arginine as a normal metabolite which is an important component of endothelium-derived relaxing factor (EDRFs). Nitric oxide, formed by endothelial cells, is taken up by vascular smooth muscle cells and causes relaxation of those smooth muscle cells with concomitant decrease in vascular resistance and blood pressure. It is now widely accepted that many naturally occurring substances which act as physiological or pharmacological vasodilators mediate all or part of their action by stimulating release of EDRFs; these substances include acetylcholine, histamine, bradykinin, leukotrienes, ADP, ATF, substance P, serotonin, thrombin and others. EDRFs are currently being intensively studied as participating in regulation of blood flow and vascular resistance. Incident to such study, a search has been carried out for compounds which inhibit nitric oxide production in the body. One compound discovered for use to obtain this effect is the arginine antagonist N.sup.G -methyl-L-arginine (Palmer, R. M. J., et al, Nature (London), 333, pp. 664-666, 1988). Administration of N.sup.G -methyl-L-arginine to guinea pigs and rabbits has been shown to increase blood pressure (Aisaka, K., et al, Biochemical and Biophysic Research Communications, Vol. 160, No. 2, pp. 881-886, 1989; Rees, D. D., et al, Proc. Natl. Acad. Sci. USA, Vol. 86. pp. 3375-3378, 1989). Very recently, it has been discovered that arginine antagonists inhibit systemic hypotension (Kilbourn, R. G. et al U.S. Ser. No. 07/406,909) and that a very effective arginine antagonist is physiologically active Ne-amino-arginine (Griffith, O. W., U.S. Ser. No. 07/406,897). It has also been discovered that the duration of the nitric oxide-mediated hypotensive response to acetylcholine is prolonged in animals infused with L-arginine (Aiaska, K., et al, Biochem. Biophys. Res. Commun. 163, 710-717, 1989).
In addition to vascular endothelium, macrophages have also been shown to produce nitric oxide in the body which is a component of their cell killing and/or cytostatic function (Iyengar, R., et al, Proc. Natl. Acad. Sci, USA, Vol. 84, pp. 6369-6373, 1987). It has also been shown in vitro that addition of arginase to cocultivation medium prevents the activated macrophage cytoxic effector mechanism (Hibbs, J. B., et al, The Journal of Immunology, Vol. 138, No. 2, 550-565, 1987).